Eczema compound patents’ herbal combination rules research based on complex system entropy clustering: A review

The aim of this study is to investigate the herbal compound patents’ combination rules of eczema. Eczema herbal compound patents (oral drugs) from the past 29 years were collected, and a database was created. Complex system entropy clustering was used to analyze the prescription rule for eczema herbal compound patents. In total, 1039 eczema herbal compound patents, including 398 Chinese herbs, were identified. Complex system entropy clustering acquired high-frequency herbs, herbal couples, and core associations. Eczema herbal compound patents are known for clearing dampness and heat, dispelling poison, evacuating wind, and invigorating and cooling blood. By using complex system entropy clustering, herbal correlation of eczema herbal compound patents can be effectively analyzed.


Introduction
Eczema is a delayed hypersensitivity reaction caused by both internal and external factors. It is characterized by a diverse symmetrical rash, intense pruritus, and recurrence of a transudative skin inflammation. Based on skin lesion development, it is classified into 3 types: acute, subacute, and chronic. According to Western medicine, eczema is caused by an interaction between inner and outer body factors associated with type I and II hypersensitivity reactions. Although it is treated with antihistamines, glucocorticoids, and immunosuppressive, a satisfactory cure has not been achieved.
Complex system-based entropy clustering is the process of extracting valuable and potential knowledge from a large amount of data, also referred to as knowledge discovery in databases. It incorporates the latest database technologies, artificial intelligence, machine learning, statistics, knowledge engineering, object-oriented methods, information retrieval, high-performance computing, and data visualization. This is a multidisciplinary field of study. Complex system-based entropy clustering is an unsupervised pattern discovery algorithm extracting a combination with the largest amount of information from massive data by self-organization. This method is mainly suitable for highly discrete data, such as herbal compounds. [1] It has been successfully applied in extracting clinical syndrome elements along with disease and syndrome. Since the traditional Chinese medical literature consists of discrete, continuous, mixed data, entropy methods based on the complex system make sense for analyzing prescription laws. This method has 2 significant benefits. It can qualitatively and quantitatively excavate the correlation between drugs and disease syndrome and symptoms drugs. Furthermore, it can excavate the core combination of doctors' experience and excavate the herbal core combination hidden in the prescription compatibility, which the clinician has not valued.
The patent literature comprises novel, creative, and useful research results. In medicine, these results are of great significance for innovation and creation. Patent information mining can transform unordered data into valuable information, revealing any hidden messages in the patent. In this study, the oral herb prescription patents of eczema treatment from the past 29 years were selected. Herbal frequency, association, and composition compatibility regularity were investigated to guide clinical prescription and new drug development.
The herbal combination pattern determined by complex system entropy clustering could enhance the accuracy of clinical prescriptions, making selecting herbal core combinations easier and more accurate.
The traditional mutual information method has 2 limitations. Firstly, the calculation of mutual information is comparatively large; hence, the mutual information method does not This article is agreed to be published.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
We allow other researchers to validate the results of this article and perform secondary analyses. All data involved in this study are reflected in the text, and there is no other storage address. The data and materials in this article are available.
consider the spatial position relationship of adjacent values. Secondly, when there is noise or the matching quality is not high, correct matching cannot be obtained. This study introduces the boundary mutual distance into the mutual information registration measure. By combining mutual information and mutual distance information, the new registration measure improves the mutual information registration measuring function, reducing the risk of the traditional maximum mutual information method falling into extremum and defining the accurate ratio of information about eczema patent compound composition.
On the basis of this study, future research will be based on the network pharmacology methods to obtain the main active ingredients of each drug pair and drug combination and their efficacy in treating eczema through TCMSP, DRAR-CPI, Genecards, OMIM, and other databases. Using Cytoscape 3.6.0 software, the active ingredient-potential target network will be constructed, and the interaction network of potential targets will be screened out along with the core targets, whose binding affinity with the active ingredients can be verified by molecular docking. An active ingredient-potential target-key pathway network will be constructed based on gene ontology and KEGG pathway enrichment analysis of potential targets. This study aims to explore the active ingredients, targets, pathways, and mechanisms of the drug pairs or drug combinations in the treatment of eczema (Fig. 1).

Collection and collation of eczema herbal compound patents
The literature collection covered the National Intellectual Property Office patent database, the Derwent World Patent Index database, the Multinational Patent Review Information Search System, The World Digital Library of Intellectual Property, traditional Chinese medicine enterprises, and related herbal intellectual property organizations. Eczema herbal compound patents with an application period between January 1993 and December 2021 were retrieved.

Database establishment
Epidata 3.1 was used to develop the information mining program. Each eligible eczema prescription patent herb was assigned a 2-valued variable. [2] When the user clicks on the Chinese herbs involved in a prescription with the mouse, he automatically assigns them the value "1." The remaining unclicked herbs were assigned the value "0" automatically. The database contained 1039 patents of compound prescriptions for eczema, including 398 commonly used Chinese herbs.

Mathematical modeling and data mining
Data mining was conducted using mathematical entropy modeling and screening out herbal pairs and core combinations with strong efficacy coherence. Complex system entropy clustering and the improved mutual information method were used to construct the research program and create the research model in order to initiate the quantitative description of the correlation coefficient of Chinese medicine. The eventual purpose was to extract the herbal couples and herbal core combinations. Mathematical modeling was used to mine the eczema prescription patent. The most relevant core combinations of Chinese herbs were screened out by mathematical calculations, comprising core herb pairs and herb teams. The improved mutual information method, complex system entropy clustering method, and unsupervised entropy hierarchical clustering method were used for data analysis and precisely described the herbal correlation coefficient and core combination extraction.
Here are the core formulas of the improved mutual information method and complex system entropy clustering method: Unsupervised hierarchical clustering can be described using the following form u l a : signifies the frequency of positive occurrences of the 2 variables Xi and Xj, and b is a real number > 1 and a penalty coefficient. δ represents the threshold value. Selecting the appropriate threshold can separate the positive correlation from the negative correlation and avoid the interference caused by incorrect data. H(X) and H(Y) denote the information entropy of X and Y, respectively, whereas H(X ∪ Y) signifies joint entropy.
The above research process can also be expressed as follows: Δµ(Xi,Xj)= In this formula, q(x i ) and q(x j ) represent the probability density function of variate X i , and the variates X j , C(X i ), and C(X j ) represent the entropy of variate X i and variate X j . C(X i , X j ) denotes the combination entropy of variate X i and variate X j , and u ij is a dimensionless quantity. When variate X i and variate X j are in perfect correlation, the value of variate u ij is 1. When variate X i and variate X j are completely independent, the value of variate u ij is 0. Generally, variate u ij is valued between 0 and 1, whereas variate u ij is equal to variate u ji . Q o (i, j) represents the positive frequency of variate X i and variate X j , b is a penalty coefficient, and δ is the threshold value.
In total, 1039 prescriptions in the database were analyzed and screened using the methods mentioned above. A total of 124 Chinese herbs with high frequency and 45 regularly used drug pairs were obtained using the improved mutual information method, and 35 groups of core combinations were obtained using complex system entropy clustering.

Results
1. The high-frequency herbs, herbal couples, and herbal core combinations are included in Tables 1, 2, and 3, respectively. 2. The effects of high-frequency herbs were observed in heat elimination, dampness clearing, detoxification, blood cooling, evacuation of wind and heat, blood circulation, soothing liver, etc. (Figs. 2 and 5). Herbal couples are made up of 2 herbs that work together synergistically to achieve better results. The couple consists of 2 herbs with similar efficacy that play a therapeutic role with mutual assistance and 2 herbs with similar efficacy that are superimposed on each other (Table 4, Fig. 4). Herbal core combinations suggest that several herbs work together and appear together in most descriptions. These combinations are expressed as drug groups with the same or similar efficiency (

Acknowledge chinese medicine on eczema
Eczema is caused by the body's weakness and the intrusion of wind, heat, and wet evil. It is divided into 3 types: acute, subacute, and chronic. Acute eczema mainly results from damp heat. The deficiency of the spleen system results in wet evil resistance, leading to subacute eczema. Chronic eczema occurs when the skin cannot be nourished due to long illnesses and blood loss. Acute eczema spreads throughout the body; chronic eczema mainly damages some parts of the body, while subacute eczema has symptoms between acute and chronic eczema. [3] The 3 types coexist in the same period, but one type dominates in most cases. The 4 pathogenic factors (damp heat, spleen weakness, long illness, and blood loss) also affect the body. Therefore, the treatment of eczema by herbal prescription must consider the 4 pathogenic factors even while concentrating on one pathogenic factor. Clinically, eczema is always stratified into 2 major cure species: damp-heat siltation and skin undernutrition for blood weakness. Medicine

Analysis of high-frequency herbs and their active pharmaceutical ingredients for treating eczema
According to the findings, herbs that clear damp heat are widely used. The number of damp heat-clearing herbs is 32 in high-frequency herbs. Damp-heat siltation eczema is treated by removing dampness and heat. When the heat proportion is greater than dampness, clearing fire and detoxification play a crucial part.
Spleen strengthening and clearing dampness play an important role when the dampness proportion is greater than the heat, whereas the dispelling of dampness by aromatic herbs will serve as adjuvant therapy. Blood weakness causes eczema, which is treated by nourishing the blood and eradicating other pathogenic factors. In most cases, numerous treatments are introduced, such as delighting the liver, dredging blood stasis, and eliminating wind evil. Calamine 69 Table 2 Drug pair and its correlation coefficient. In this research, the high-frequency Chinese herbs had excellent clinical effects on eczema. The use of Sophora flavescens, the dried root of the leguminous plant Sophora flavescens, was the most frequent (Table 1). Its taste is extremely bitter, and its property is cold. It is therapeutic in the meridian systems of the heart, liver, stomach, large intestine, and bladder. It effectively clears heat and dampness, dispelling wind and arresting itch, killing parasites, and eliminating urine. It is always used in treating itchy skin, pustular sores, scabies, and leprosy. In eczema, it usually acts as a master herb with the maximum dose. According to traditional Chinese medicine theory, its effect of removing dampness and heat is achieved by acting on the mentioned organs. Alkaloids (matrine, oxymatrine, noxysophocarpine, sophoridine, I-somatrine, sophoranol, anagyrine, baptifoline, kuraridinol, kurarinol, neokurarinol, norkurarinol, and isokurarinone) are the primary chemical compounds of S. flavescens used in treating eczema.

Herbal pair
The anti-allergy properties of matrine can reduce the release of allergy mediators; therefore, it is used as an immunosuppressant. Matrine has an antibacterial effect both inside and outside the body. Its intensity inside the body is comparable with that of chloramphenicol, and the alcohol extract has an antitrichomoniasis effect outside the body. [4] Furthermore, matrine and oxymatrine have inhibitory effects on immune function in mice. Intramuscular injection of oxymatrine can inhibit passive or active allergic skin reactions in rabbits and rats. Moreover, oxymatrine can significantly inhibit exudative inflammation induced by croton oil, carrageenan, and glacial acetic acid.
Traditionally, Cortex Phellodendri Chinensis herb is used to clear heat and wet turbidity. In addition to its ability to pyrolyze and detoxify, it tastes bitter and regulates the kidney, bladder, and large intestine. Its primary ingredients are berberine, phello dendrine, magnoflorine, jatrorrhizine, palmatine, menisperine, obacunone, etc. It has an antibacterial effect with a strong inhibitory effect in vitro on Staphylococcus aureus, Bacillus anthracis, Helicobacter, and hemolytic streptococcus, and its active antibacterial ingredient is berberine. Additionally, Cortex Phellodendri Chinensis has antifungal effects. The ethanol extract has strong antifungal activity against Cryptococcus neoformans and red psoriasis, and its effect is stronger than nystatin. Furthermore, it has an antitrichomonas effect, and its decoction has an inhibitory effect on Trichomonas vaginalis. Its decoction can increase the number of spleen plaque-forming cells in mice, inducing immune function. [5] Licorice herb efficiently supplements spleen function, relieves pain, and reconciles herbal performance. It tastes sweet and has a distinct effect on the meridian systems of the heart, lung, spleen, and stomach. Glycyrrhiza polysaccharide, a macromolecular polysaccharide extracted from licorice, has a strong inhibitory effect on bacteria [6] and can increase the activity of natural killer cells and antibody-dependent cell-mediated cytotoxicity both inside and outside the body. It can activate the lymphocyte proliferation of mice, selectively enhance the additive power and activity of helper T lymphocytes, and regulate multiple cytokine production and secretion. [7] The anti-allergic effect of licorice is mostly due to glycyrrhizin, which can significantly prevent the release of histamine, acetylcholine, and other allergic compounds, thus inhibiting certain allergic reactions. [8] Glycyrrhizin can considerably reduce the expression level of inflammatory factors, the activity of colon pulp peroxidase, and Table 3 Herbal core combinations.

No
Herbal core combination lipid-protein denaturation, and organ damage due to active oxidation substances. [9] Saposhnikovia divaricata Schischk removes evil (wind and dampness evil) from the body surface and relieves pain. It has an evident effect on the meridian systems of the bladder, liver, and spleen. Its decoction significantly increases the pain threshold of mice and has a sedative and analgesic effect. [10,11] Moreover, its volatile oil has an analgesic effect in each dose group. The analgesic and sedative effects of S. divaricata Schischk in eczema treatment are the results of synergy among various chemical components, such as color ketone, coumarin, polyacetylene, volatile oil, etc. [12,13]

Herbal pairs and combinations are simple and effective in treating eczema
Eczema can be effectively treated with herbal combinations and pairs. The findings of this study have revealed that the herbal pairs and their core combinations for the treatment and prevention of eczema are simple and basic traditional Chinese medical compatibility, including spleen strengthening, hot dampness clearing, blood circulation, cooling, detoxification, inducing resuscitation, attacking evil, dispelling wind, etc.
A drug pair is a combination of 2 herbs, which is the most basic form of an herbal compound. With reasonable collocation, it can improve or change the efficiency of monoherbs and guide the action
Atractylodes Lancea (Thunb.) DC and Cortex Dictamni have anti-inflammatory properties. [19,20] Oxidizing matrine inhibits macrophage phagocytosis and prevents the release of histamine for mast cell degranulation. [21] Poria has a strong inhibitory effect on cellular as well as humoral immunity. [22,23] Water extract from Wolfiporia cocos can prevent mice contact with dermatitis and toe inflammation. [24,25] Therefore, the combination of Atractylodes Lancea (Thunb) DC, S. flavescens, Cortex Dictamni, and Wolfiporia cocos can treat eczema with an anti-inflammatory and immunization effects.
Herbal pairs and core combinations used in this experiment were taken from an ancient classical compound, Ermiao pill (Atractylodes Lancea + Cortex Phellodendri Chinensis), created in the last Yuan Dynasty. In hot and humid immersions, it can remove dampness and heat. Xiaofeng powder (S divaricata Schischk + Periostracum Cicadae + Atractylodes Lancea) was created in Ming·Waike Zhengzong, which has antipyretic, dehumidifying, wind evil-removing, and blood-nourishing. It can treat eczema with several symptoms, such as intense itching, obvious heat, and severe eczema all over the body, and with 3 kinds of evil, such as heat, humidity, and wind. The Shenling Baizhu powder (Wolfiporia cocos + Coix Seed + Chinese Yam + AtractyLodes macrocephala) was created in Song·Taiping Huimin Heji Jufang. It strengthens the spleen, promotes Qi function, and eliminates humidity. If eczema patients have spleen deficiency symptoms, such as thinning, pathological yellow complexion, fatigue, and stool accompanied by indigestible food can benefit from Shenling Baizhu powder. Additionally, Erchen pill (Tangerine skin + Wolfiporia cocos + Licorice) was created in Song·Taiping Huimin Heji Jufang. As well as clearing dampness and phlegm, it coordinates stomach and Qi functions. It is always used to treat eczema patients with phlegm wet symptoms, such as white phlegm, chest, and abdomen bulging, heavy limbs, white tongue coating, etc.

Conclusion
The findings of this study confirmed the following: the main pathogen of eczema is wet evil condensed in the body; therefore, the elimination of dampness is vital for its treatment. Blood and Qi may sludge in the body if wet evil deposits remain in the body for an extended period of time. The sludging of Qi and blood must transform into heat evil. Therefore, hot dampness also plays an important role in eczema pathogenesis.
Spleens and stomachs play an important role in the immune system, so the weakness of either will adversely affect immune function. Therefore, although eczema manifests in the skin, the source of the disease is in the spleen and stomach. The deficiency of the spleen (soil of the 5 elements) deteriorates the Qi operation mechanism, and the evil of humidity and heat is embodied. Having humidity and heat makes it easy for wind evil to attack. Wind, humidity, and heat result in rashing. Therefore, it is necessary to pay attention to the nourishment of the spleen (soil) to restrict humidity and heat. Some cases require removing evil (heat, dampness, and wind) as the main treatment, with strengthening the spleen and stomach can be used as an adjunctive treatment. In others, strengthening the spleen and stomach plays a major role in dissipating evil. In most cases, both the internal and external treatments are simultaneously applied.
Based on these results, network pharmacology will be used to discover each drug pair (combination)'s main active ingredients     Acute or subacute eczema, stagnation of dampness and heat, lver and gallbladder fire stasis.
(Continued ) www.md-journal.com   and their efficacy in treating eczema, and to investigate their interactions. Key pathways were identified using molecular docking methods to verify their binding affinity with active ingredients, which enabled comprehensive and systematic exploration of active ingredients, targets, pathways, and action mechanisms of drug pairs or combinations in the eczema treatment.